The phorbol esters, together with the structurally related ingenol and resiniferonol esters, are diterpene derivatives from plants of the families Euphorbiaceae and Thymeleaceae (Evans, F. J. and Taylor, S. E. (1983) Fortshr. d. Chem. organ. Naturst , Vol. 44, pp. 1-99; Hecker, E. (1978) In Carcinogenesis, Mechanisms of Tumor Promotion and Cocarcinogenesis (T. J. Slaga, A. Sivak and R. K. Boutwell, Eds.), Vol. 2, pp. 11-48, Raven Press, N.Y.). The phorbol esters have been the objects of intense research interest due to their tumor promoting activity (Hecker, E. (1968) Cancer Res., Vol. 28, pp. 2238-2349). More recently, the description of the role of the phorbol esters as modulators of protein kinase have been studied (Ashendel, C. L. (1985) Biochim. Biophys. Acta, Vol. 822, pp. 219-242; Blumberg, P. M. (1988) Cancer Res., Vol. 48, pp. 1-8). These compounds are also potent irritants, and their isolation from natural sources has been guided by the activity of organic extracts of the plants in a mouse ear reddening assay (Hecker, E., Immich, H., Bresch, H. and Schairer, H.-U. (1966) Z. Krebsforsch, Vol. 68, pp. 366-374). Resiniferatoxin (RTX), a resiniferonol ester, was isolated from Euphoribia resinifera, E. poissonii and E. unispina on the basis of this activity (Hergenhahn, M., Adolph, W. and Hecker, E. (1975) Tet. Lett. Vol. 19, pp. 1595-1598; Evans, F. J. and Schmidt, R. J. (1976) Phytochemistry, Vol. 15, pp. 333-335).
For the phorbol esters, esterification of the exocyclic hydroxyl at C20 causes marked loss of activity (Hecker, E. (1978) Carcinogenesis, Mechanisms of Tumor Promotion and Cocarcinogenesis. Vol. 2, pp. 11-48, Raven Press, New York). RTX differs from the tumor promoting resiniferonol derivatives in that it is esterified at this position. Structure-activity analysis indicates that this substituent, 4-hydroxy-3-methoxyphenylacetate, plays an essential role in determining activity. (Adolph, W., Sorg, B., Hergenhahn, M. and Hecker, E. (1982) J. Nat. Prod., Vol. 45, pp. 347-354; Schmidt, R. J. and Evans, F. J. (1979) Inflammation, Vol. 3, pp. 273-280). Capsaicin, the irritant component in fruit of various species of Capsicum, also possesses a 4-hydroxy-3-methoxyphenyl substituent which is critical for activity (Szolcsanyi, J. and Jancso-Gabor. A, (1975), Arzneim-Forsch, Vol. 25, pp. 1877-1881).
One well documented action of capsaicin is to produce a dramatic fall in body temperature (Jancso-Gabor, A., Szolcsanyi, J. and Jancso, N. (1970), J. Physiol, Vol. 208, pp. 449-459; Szikszay, M., Obal, F. Jr., and Obal, F. (1982) Naunyn-Schmiedeberg's Arch. Pharmacol, Vol. 320, pp. 97-100). The inventors have explored possible homology between these two classes of irritant compounds to determine if RTX has a role in thermoregulation and to compare these effects with those of capsaicin.
U.S. Pat. No. 4,716,179 by Hecker et al discloses the use of a non-irritating or slightly irritating and/or tumor promoting diterpene alcohol and of derivatives thereof as antineoplastic preparations. Resinferatoxin was found to have neither a curative nor a significant tumor-inhibiting effect in carcinomas.